The present invention, in some embodiments thereof, relates to regulatory immune cells with enhanced apoptotic activity and, more particularly, but not exclusively, to the use thereof for immunomodulation, for treating or for preventing immune related disorders.
Disorders associated with regulatory immune cells include inter alia autoimmune diseases such as for example diabetes type 1, multiple sclerosis, inflammatory bowel disease, chronic inflammatory diseases such as infections, cancer, induced disorders such as graft versus host disease and induced transplant tolerance.
Immunotherapy is a highly desired treatment of such human diseases. The basis for immunotherapy is the manipulation of the immune response, particularly the responses of T cells, which possess complex and subtle systems for controlling their interactions, utilizing numerous receptors and soluble factors for the process. Healthy immune system generally reacts against harmful pathogens while remaining specifically tolerant to autologous tissues. Failure of such self tolerance can result in autoimmune disease, while a failure to respond appropriately can lead to infection, and may result in the growth of tumor cells. For most autoimmune diseases and undesired immune responses, no effective therapeutic agents exist. For example, current therapeutic strategies are often based on chemically induced immunosuppression, which can result in undesirable side effects on the kidney and other organs.
Deficiency or dysfunction of regulatory immune cells has been implicated in the pathogenesis of these diseases. In particular, the suppressor cells were shown to have a particularly important role in maintaining immune system homeostasis. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance.
Previous reports have indicated that T regulatory cell elicit suppression of reactive immune cells by several mechanisms including modulation of the cytokine environment at the site of inflammation and by suppression of proliferation and/or cytokine production by effector T cells. The mechanism which involves physical elimination of cytotoxic cells is unanimously considered as a minor mechanism of suppression within the extensive data relating to the functional inhibition of naïve and pathogenic T cells [von Boehmer H. Nat Immunol (2005) 6:338-44; Shevach E M. Immunity (2009) 30:636-645; Miyara M. and Sakaguchi S. Trends Mol Med (2007) 13:108-16; Askenasy N. et al. Autoimmun Rev (2008) 7:370-5; Sojka D K et al. Immunology (2008) 124:13-22; Vignali et al. Nat Rev Immunol (2008) 8: 523-32].
The use of T regulatory cells has been previously implicated for the treatment of autoimmune diseases, these are summarized infra:
U.S. Patent Application No. 20100310588 (to Bluestone J. A. et al.) discloses methods for producing autoantigen-specific regulatory T cells and methods for use of same. According to the teachings of 20100310588, T cells are derived from a subject or from a donor, CD25+CD4+ T regulatory (Treg) cells are selected by immuno-selection and cell sorting, the Treg cells are expanded ex vivo by the use of a TCR/CD3 activator (e.g. anti-CD3 antibody), a TCR costimulator activator (e.g. anti-CD28 antibody) and IL-2 and the expanded population of Treg cells are adoptively transferred to a subject for treatment of autoimmune responses (e.g. diabetes, GVHD, Lupus, etc.).
U.S. Patent Application No. 20100260781 (to Murray L. A.) provides methods and compositions for expanding T regulatory cells ex vivo or in vivo using one or more serum amyloid P(SAP) agonists (e.g. SAP polypeptide). According to their teachings, the use of SAP agonists enriches for regulatory T cells and thus promotes regulatory T cell-mediated suppression of autoimmune disorders or conditions (e.g. diabetes, graft rejection, GVHD, etc.).
U.S. Patent Application No. 20100092488 (to Suzumura A. et al.) provides methods for increasing the number of regulatory T cells by inhibiting midkine (MK). 20100092488 further provides methods for treatment or prevention of diseases (e.g. autoimmune diseases such as diabetes, lupus etc.) associated with the functional disorder of regulatory T cells comprising the administration of a midkine inhibitor.
U.S. Patent Application No. 20090142308 (to Orban T. et al.) provides methods for treating autoimmune diseases (e.g. diabetes) by inducing autoantigen-specific regulatory CD4+ T cells. According to the teachings of 20090142308, treating an autoimmune disease is effected by first administering to the subject a composition comprising an autoantigen (e.g. insulin) and an oil-and-water adjuvant. Next, a blood sample comprising PBMCs is obtained from the subject and autoantigen-specific regulatory T cells are isolated therefrom. The autoantigen-specific regulatory T cells may then be expanded ex vivo to obtain an adequate amount of cells for treatment and the autoantigen-specific regulatory T cells are then administered back to a subject.
PCT Publication No. 2010/017220 (to Kambayashi T. et al.) discloses methods of expanding and enriching a regulatory T-cell population by contacting a leukocytes population having antigen-presenting cells with a granulocyte-macrophage colony stimulating factor (GMCSF), interleukin-3 (IL-3) and/or interleukin-5 (IL-5). The regulatory T cells disclosed therein may be used for suppressing naïve T-cells in a subject and subsequently for the treatment of autoimmune diseases.
In addition, depletion of autoreactive T cells through apoptosis as a means of preventing autoimmune diseases has also been contemplated. Jin et al. [Jin et al. Gene Therapy (2004) 11:982-991] disclosed the use of a CTLA4-Fas ligand (FasL) fusion protein, which simultaneously stimulates the Fas-mediated pathway and blocks co-stimulation of the T cell receptor, for apoptosis of peripheral T lymphocytes.